Polyene oxazoles and processes for their preparation

Abstract

Polyene oxazoles of the following formula wherein R 3 is selected from H and methyl, are disclosed. Such compounds, and pharmaceutically acceptable salts thereof, may be used in the inhibition of tumor cell growth. The polyene oxazoles and their pharmaceutically acceptable salts may be formulated as pharmaceutical compositions with pharmaceutically acceptable carriers for use in the inhibition of tumor cells. The polyene oxazoles may be obtained from strains of Streptomyces sparsogenes , such as strain 022 having deposit number IDAC 270504-04.

1. A compound of the formula 
       
         
           
           
               
               
           
         
       
       wherein R 3  is selected from H and methyl; or a pharmaceutically acceptable salt thereof. 
     
     
       2. A compound of the formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       3. A compound of the formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       4. A pharmaceutical composition comprising compound of the formula 
       
         
           
           
               
               
           
         
       
       wherein R 3  is selected from H and methyl; or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier. 
     
     
       5. A pharmaceutical composition comprising a compound of the formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier. 
     
     
       6. A pharmaceutical composition comprising a compound of the formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier. 
     
     
       7. A polyene oxazole obtained by a method comprising
 (a) cultivating a  Streptomyces sparsogenes  strain, wherein said cultivation is performed under aerobic conditions in a nutrient medium comprising at least one source of carbon atoms and at least one source of nitrogen atoms; and 
 (b) isolating a polyene oxazole from the strain cultivated in step (a), wherein said polyene oxazole is a compound of the formula 
 
       
         
           
           
               
               
           
         
       
     
     
       8. A polyene oxazole obtained by a method comprising
 (a) cultivating a  Streptomyces sparsogenes  strain, wherein said cultivation is performed under aerobic conditions in a nutrient medium comprising at least one source of carbon atoms and at least one source of nitrogen atoms; and 
 (b) isolating a polyene oxazole from the strain cultivated in step (a), wherein said polyene oxazole is a compound of the formula 
 
       
         
           
           
               
               
           
         
       
     
     
       9. A process for making the compound of  claim 1 , comprising the steps of cultivation of a  Streptomyces sparsogenes  strain, in a nutrient medium comprising at least one source of carbon atoms and at least one source of nitrogen atoms, and isolation and purification said compound. 
     
     
       10. The process of  claim 9 , wherein said  Streptomyces sparsogenes  strain is NRRL 2940 or a mutant thereof. 
     
     
       11. The process of  claim 10 , wherein said mutant is strain [S03]022 (deposit accession number IDAC 270504-04). 
     
     
       12. The process of  claim 9  wherein cultivation occurs under aerobic conditions. 
     
     
       13. The process of  claim 9  wherein said nutrient medium is a media selected from the group consisting of media DA, DZ, ET, JA, MY, NA, QB and VB as set forth in the table below: 
       
         
           
                 
                 
                 
                 
                 
                 
                 
                 
                 
               
                     
                 
                   Component 
                   DA 
                   DZ 
                   ET 
                   JA 
                   MY 
                   NA 
                   QB 
                   VB 
                 
                     
                 
                     
                 
                 
                 
                 
                 
                 
                 
                 
                 
                 
               
                   Glucose 
                   10 
                   5 
                     
                     
                     
                     
                   6 
                   10 
                 
                   Sucrose 
                     
                     
                     
                     
                     
                     
                     
                   20 
                 
                   Maltose 
                     
                     
                     
                     
                   4 
                 
                   Cane molasses 
                   10 
                   10 
                   60 
                     
                     
                   10 
                     
                   20 
                 
                   Soluble starch 
                   5 
                   15 
                   20 
                     
                     
                     
                   5 
                 
                   Corn starch 
                     
                     
                     
                   30 
                 
                   Potatoe dextrin 
                   20 
                 
                   Corn steep solids 
                   5 
                     
                     
                     
                     
                     
                   2.5 
                 
                   Corn steep liquid 
                     
                     
                     
                   15 
                 
                   Malt extract 
                     
                     
                     
                   35 
                   10 
                 
                   Yeast extract 
                     
                     
                     
                     
                   4 
                 
                   Pharmamedia 
                     
                     
                     
                   15 
                     
                     
                   5 
                 
                   Glycerol 
                   10 
                     
                     
                     
                     
                   20 
                 
                   Soybean flour 
                   5 
                 
                   Soytonpeptone 
                     
                     
                     
                     
                     
                     
                     
                   5 
                 
                   Fish meal 
                     
                   10 
                   20 
                 
                   Bacto-peptone 
                     
                     
                     
                     
                     
                   1 
                 
                   MgSO 4 •7H 2 O 
                   0.5 
                 
                   CaCO 3 * 1   
                   3 
                   5 
                   2 
                   2 
                     
                   4 
                     
                   2.5 
                 
                   FeCl 2 •4H 2 O 
                   0.1 
                 
                   Nal 
                     
                     
                   0.5 
                 
                   ZnCl 2   
                   0.1 
                 
                   MnCl 2 •4H 2 O 
                   0.1 
                 
                   CuSO 4 •5H 2 O 
                     
                     
                   0.1 
                 
                   Phytic acid 
                   1 
                 
                   Casamino acid 
                     
                     
                     
                     
                     
                   5 
                 
                   Porflo oil 
                     
                     
                     
                     
                     
                     
                   2 
                 
                     
                 
                   Ingredients are in gm/L The pH is adjusted to 7 except where indicated 
                 
                   * 1 pH adjusted to 7.3 prior to the addition of CaCO 3 . 
                 
             
                
                
                
               
               
                
               
            
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
       14. The process of  claim 9  wherein said cultivation is carried out at a temperature ranging from 18° C. to 40° C. 
     
     
       15. The process of  claim 9  wherein said cultivation is carried out at a pH ranging from 6 to 9. 
     
     
       16.  Streptomyces sparsogenes  having IDAC accession number 270504-04.